title: Saturable human neopterin response to interferon-α assessed by a pharmacokinetic-pharmacodynamic model.
abstract: BACKGROUND
  In this study, we developed a pharmacokinetic (PK)- pharmacodynamic (PD) model of a new sustained release formulation of interferon-α-2a (SR-IFN-α) using the blood concentration of IFN-α and neopterin in order to quantify the magnitude and saturation of neopterin production over time in healthy volunteers. The SR-IFN-α in this study is a solid microparticular formulation manufactured by spray drying of a feeding solution containing IFN-α, a biocompatible polymer (polyethylene glycol) and sodium hyaluronate.
  
  
  METHODS
  The full PK and PD (neopterin concentration) datasets from 24 healthy subjects obtained after single doses of 9, 18, 27 and 36 MIU of subcutaneous SR-IFN-α were used to build the mixed-effect model using NONMEM (version 7.2) with the GFORTRAN compiler.
  
  
  RESULTS
  A one-compartment model with first-order elimination and a mixture of zero- and first-order absorption was chosen to describe the PK of SR-IFN-α. The time-concentration profile of neopterin, the PD marker, was described by a turnover model combined with a single transit compartment. The saturable pattern of the neopterin response blurring the dose-response relationship of SR-IFN-α was addressed by introducing the concept of the EC50 increasing over time.
  
  
  CONCLUSIONS
  The PK-PD model of SR-IFN-α developed in this study has presented a quantitative tool to assess the time-course of a saturable neopterin response in humans.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul St, Mary's Hospital, 222, Banpodaero, Seocho-gu, Seoul, Korea. yimds@catholic.ac.kr.
authors.forename: Sangil
authors.initials: S
authors.lastname: Jeon
authors.forename: Jae-Hyeon
authors.initials: JH
authors.lastname: Juhn
authors.forename: Seunghoon
authors.initials: S
authors.lastname: Han
authors.forename: Jongtae
authors.initials: J
authors.lastname: Lee
authors.forename: Taegon
authors.initials: T
authors.lastname: Hong
authors.forename: Jeongki
authors.initials: J
authors.lastname: Paek
authors.forename: Dong-Seok
authors.initials: DS
authors.lastname: Yim
mesh_terms: D003710:Demography; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D019798:Neopterin / Q000097:blood*; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors; D055815:Young Adult
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D019798:Neopterin